EDITORIAL COMMENT
Highest Dominant Frequencies in Atrial Fibrillation
A New Target for Ablation?*
Moussa Mansour, MD, FACCb,*
Cardiac Arrhythmia Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
* Reprint requests and correspondence: Dr. Moussa Mansour, Cardiac Arrhythmia Unit, Massachusetts General Hospital, Gray 109, 55 Fruit Street, Boston, Massachusetts 02114 (Email: mmansour{at}partners.org).
Until recently, the most widely accepted mechanism of atrial fibrillation (AF) was the "multiple wavelet" hypothesis as described by Moe and Abildskov (1) in 1959. The discovery by Haissaguerre et al. (2) in 1998 that focal ablation could eliminate paroxysmal AF in selected patients represented a major therapeutic advance. A more important consequence of that discovery was the revival of the concept that AF could result from a rapidly firing focus. This theory was described in 1925 by Sir Thomas Lewis (3), who observed that "... fibrillation, like flutter, may also on occasion be terminated in the auricle by cold or pressure very locally applied." Additional support for this alternative view came later from Scherf et al. (4,5), who used local application of aconitine to induce AF and then demonstrated that obliteration of the site of aconitine application resulted in the termination of AF. This concept initially was not accepted by electrophysiologists, perhaps because of the limited investigative methodologies available at that time, which prevented exhaustive characterization of electrical wave propagation. With the development of high-resolution mapping techniques such as optical mapping, this task became achievable. A series of studies from the laboratory of Jalife et al. (6–10) described vortex-like re-entry (rotors) around minuscule cores, with high-frequency periodic activity in the posterior left atrium and the pulmonary vein ostia. Rapid and successive electrical impulses emanating from these rotors propagate throughout the atria and interact with functional and/or anatomical obstacles, leading to fragmentation and wavelets formation. This "fibrillatory conduction" results in the seemingly random electrical activity that characterizes AF.
The report by Lin et al. (11) in this issue of the Journal describes frequency gradients in different types of paroxysmal AF. The concept of frequency gradient has been reported previously. A left-to-right gradient was first demonstrated in animal models of acute AF (9). A more recent study demonstrated the presence of a left-to-right frequency gradient in patients with paroxysmal AF (12). However, the important and novel finding in the report by Lin et al. (11) is that the highest dominant frequency is not always in the left atrium but shifts to the right atrium when AF is initiated in the superior vena cava. This discovery represents yet another strong validation for mother rotors and fibrillatory conduction as a mechanism of atrial fibrillation. The rotors initiating and maintaining AF operate at a very high frequency. The rest of the atria cannot follow in a 1:1 fashion and interatrial and intraatrial conduction block results in reduction of the frequency in areas far from the site of AF origin.
A rapidly firing focus with fibrillatory conduction and a resulting frequency gradient clearly seems to be the underlying mechanism of AF in some patients. Important unanswered questions include whether or not this mechanism explains AF in all patients and, more specifically, whether this mechanism underlies both paroxysmal and permanent AF. In addition, it remains to be determined whether AF in humans can be consistently eliminated by ablation of areas of highest dominant frequencies. Thus far, the existing evidence from human and animal studies supports the role of a rapidly firing focus in AF. One animal study in dogs with chronic AF demonstrated that local ablation of areas of shortest cycle length in the posterior left atrium caused termination of the arrhythmia (13). A recent study by Sanders at al. (14) reported that ablation of sites of high dominant frequencies resulted in prolongation of AF cycle length and termination of this arrhythmia in a large percentage of patients. The lower success rate of pulmonary vein isolation in patients with persistent or permanent AF compared with paroxysmal AF does not refute the concept of rapidly firing foci and fibrillatory conduction as a mechanism of AF. The lower success rate in this group of patients may be explained by the fact that these patients often have left atrial disease, resulting in electrophysiological and anatomic heterogeneity, which enables the formation of stable rotors in areas outside the pulmonary veins, such as the posterior, inferior, and septal parts of the left atrium, which could drive AF. In this situation, one would expect that frequency gradients would be less prominent because of the increased numbers of rotors. The presence of foci of rapid electrical activity in areas outside the pulmonary veins also may explain the increased success rate with ablation strategies using large left atrial encirclement lesions of the pulmonary veins (15–17), as well as ablation of areas of rapid fractionated electrograms (18). These lesions sets may encompass areas in the atria that could harbor rapidly firing foci.
Atrial fibrillation increasingly is being recognized as a deterministic process resulting from rapidly firing foci and fibrillatory conduction rather than a fundamentally turbulent and self-sustaining process. More studies are needed to confirm the role of high-frequency areas in driving and sustaining AF. In addition, the development of newer technologies incorporating methods of frequency analysis, such as the fast Fourier transform, to guide rapid identification and catheter ablation of high-frequency sites will be of utmost importance in furthering the exploration of the dominant frequency hypothesis.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
b Dr. Mansour has received research grants from Medtronic, St. Jude Medical, and Bard Electrophysiology.
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References
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1. Moe GK, Abildskov JA. Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge Am Heart J 1959;58:59-70.[CrossRef][Web of Science][Medline]2. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins N Engl J Med 1998;339:659-666.[Abstract/Free Full Text] 3. Lewis T. The Mechanism and Graphic Registration of the Heart Beat. 3rd edition. London: Shaw; 1925. pp. 319-374. 4. Scherf D. Studies on auricular tachycardia caused by aconitine administration Proc Exp Biol Med 1947;64:233-239.[CrossRef] 5. Scherf D, Romano FJ, Terranova R. Experimental studies on auricular flutter and auricular fibrillation Am Heart J 1958;36:241-251.[CrossRef] 6. Jalife J, Berenfeld O, Skanes AC, Mandapati R. Mechanisms of atrial fibrillationmother rotors or multiple daughter wavelets, or both?. J Cardiovasc Electrophysiol 1998;9:S2-S12.[Web of Science][Medline] 7. Skanes AC, Mandapati R, Berenfeld O, Davidenko JM, Jalife J. Spatiotemporal periodicity during atrial fibrillation in the isolated sheep heart Circulation 1998;98:1236-1248.[Abstract/Free Full Text] 8. Mandapati R, Skanes AC, Berenfeld O, Chen J, Jalife J. Stable microreentrant sources as a mechanism of atrial fibrillation in the isolated sheep heart Circulation 2000;101:194-199.[Abstract/Free Full Text] 9. Mansour M, Mandapati R, Berenfeld O, et al. Left-to-right gradient of atrial frequencies during acute atrial fibrillation in the isolated sheep heart Circulation 2001;29:2631-2636. 10. Jalife J, Berenfeld O, Mansour M Mother rotors and fibrillatory conductiona mechanism of atrial fibrillation, Cardiovasc Res. 2002;54:204-216. 11. Lin Y-J, Tai C-T, Kao T, et al. Frequency analysis in different types of paroxysmal atrial fibrillation J Am Coll Cardiol 2006;47:1401-1407.[Abstract/Free Full Text] 12. Lazar S, Dixit S, Marchlinski F, Callans D, Gerstenfeld E. Presence of left-to-right atrial frequency gradient in paroxysmal but not persistent atrial fibrillation in humans Circulation 2004;110:3181-3186.[Abstract/Free Full Text] 13. Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial pacingstructural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation 1995;91:1588-1595.[Abstract/Free Full Text] 14. Sanders P, Berenfeld O, Hocini M, et al. Spectral analysis identifies sites of high-frequency activity maintaining atrial fibrillation in humans Circulation 2005;112:789-797.[Abstract/Free Full Text] 15. Pappone C, Oreto G, Rosanio S, et al. Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablationefficacy of an anatomic approach in a large cohort of patients with atrial fibrillation. Circulation 2001;104:2539-2544.[Abstract/Free Full Text] 16. Oral H, Scharf C, Chugh A, et al. Catheter ablation for paroxysmal atrial fibrillationsegmental pulmonary vein ostial ablation versus left atrial ablation. Circulation 2003;108:2355-2360.[Abstract/Free Full Text] 17. Mansour M, Ruskin J, Keane D. Efficacy and safety of segmental ostial versus circumferential extra-ostial pulmonary vein isolation for atrial J Cardiovasc Electrophysiol 2004;15:532-537.[Web of Science][Medline] 18. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillationmapping of the electrophysiologic substrate. J Am Coll Cardiol 2004;43:2054-2056.[Free Full Text]
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